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Research Article

NF-κB inhibitor targeted to activated endothelium demonstrates a critical role of endothelial NF-κB in immune-mediated diseases

Bettina Sehnert, Harald Burkhardt, Johannes T. Wessels, Agnes Schröder, Michael J. May, Dietmar Vestweber, Jochen Zwerina, Klaus Warnatz, Falk Nimmerjahn, Georg Schett, Stefan Dübel, and Reinhard Edmund Voll
PNAS first published September 23, 2013; https://doi.org/10.1073/pnas.1218219110
Bettina Sehnert
aDepartment of Rheumatology and Clinical Immunology and Centre of Chronic Immunodeficiency, University Medical Centre and University of Freiburg, 79106 Freiburg, Germany;
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Harald Burkhardt
bDivision of Rheumatology, Department of Internal Medicine II and Fraunhofer IME-Project-Group Translational Medicine and Pharmacology, Johann Wolfgang Goethe University Frankfurt am Main, 60590 Frankfurt am Main, Germany;
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Johannes T. Wessels
cCentral Core Facility “Molecular and Optical Live Cell Imaging”, Department of Nephrology and Rheumatology, University Medicine, 37075 Göttingen, Germany;
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Agnes Schröder
dInterdisciplinary Center of Clinical Research, Research Group N2, Nikolaus Fiebiger Center of Molecular Medicine, University of Erlangen-Nürnberg, 91054 Erlangen, Germany;
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Michael J. May
eSchool of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104;
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Dietmar Vestweber
fMax-Planck Institute for Molecular Biomedicine, 48149 Münster, Germany;
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Jochen Zwerina
gDepartment of Internal Medicine 3, University of Erlangen-Nürnberg, 91054 Erlangen, Germany;
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Klaus Warnatz
aDepartment of Rheumatology and Clinical Immunology and Centre of Chronic Immunodeficiency, University Medical Centre and University of Freiburg, 79106 Freiburg, Germany;
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Falk Nimmerjahn
hDivision of Genetics, Department of Biology, University of Erlangen-Nürnberg, 91058 Erlangen, Germany; and
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Georg Schett
gDepartment of Internal Medicine 3, University of Erlangen-Nürnberg, 91054 Erlangen, Germany;
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Stefan Dübel
iInstitute of Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, 38106 Braunschweig, Germany
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Reinhard Edmund Voll
aDepartment of Rheumatology and Clinical Immunology and Centre of Chronic Immunodeficiency, University Medical Centre and University of Freiburg, 79106 Freiburg, Germany;
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  • For correspondence: reinhard.voll@uniklinik-freiburg.de
  1. Edited by Florian R. Greten, Technical University of Munich, Munich, Germany, and accepted by the Editorial Board August 2, 2013 (received for review October 18, 2012)

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Significance

The transcription factor NF-κB is crucially involved in the pathogenesis of inflammatory diseases and represents a target for treatment. However, a general blockade of NF-κB by small-molecule inhibitors is associated with serious side effects due to the importance of NF-κB in cellular survival and function of various organs. This paper demonstrates that cell type-specific NF-κB inhibition can be achieved using multi-modular fusion proteins, which exclusively target activated endothelial cells. Inhibition of NF-κB within activated endothelium potently ameliorated peritonitis and arthritis in mice, indicating that endothelial NF-κB might be a valid target in inflammatory diseases. Importantly, this strategy enables the targeting of other cell types and intracellular signaling pathways.

Abstract

Activation of the nuclear transcription factor κB (NF-κB) regulates the expression of inflammatory genes crucially involved in the pathogenesis of inflammatory diseases. NF-κB governs the expression of adhesion molecules that play a pivotal role in leukocyte–endothelium interactions. We uncovered the crucial role of NF-κB activation within endothelial cells in models of immune-mediated diseases using a “sneaking ligand construct” (SLC) selectively inhibiting NF-κB in the activated endothelium. The recombinant SLC1 consists of three modules: (i) an E-selectin targeting domain, (ii) a Pseudomonas exotoxin A translocation domain, and (iii) a NF-κB Essential Modifier-binding effector domain interfering with NF-κB activation. The E-selectin–specific SLC1 inhibited NF-κB by interfering with endothelial IκB kinase 2 activity in vitro and in vivo. In murine experimental peritonitis, the application of SLC1 drastically reduced the extravasation of inflammatory cells. Furthermore, SLC1 treatment significantly ameliorated the disease course in murine models of rheumatoid arthritis. Our data establish that endothelial NF-κB activation is critically involved in the pathogenesis of arthritis and can be selectively inhibited in a cell type- and activation stage-dependent manner by the SLC approach. Moreover, our strategy is applicable to delineating other pathogenic signaling pathways in a cell type-specific manner and enables selective targeting of distinct cell populations to improve effectiveness and risk–benefit ratios of therapeutic interventions.

  • cell targeting
  • intracellular signaling
  • autoimmune disorders
  • mouse models
  • inhibit inflammation

Footnotes

  • ↵1B.S. and H.B. contributed equally to this work.

  • ↵2To whom correspondence should be addressed. E-mail: reinhard.voll{at}uniklinik-freiburg.de.
  • Author contributions: B.S., H.B., S.D., and R.E.V. designed research; B.S., J.T.W., A.S., K.W., and R.E.V. performed research; M.J.M. and D.V. contributed new reagents/analytic tools; B.S., H.B., J.T.W., D.V., J.Z., F.N., G.S., and R.E.V. analyzed data; F.N. provided G6PI serum; and B.S., H.B., M.J.M., and R.E.V. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission. F.R.G. is a guest editor invited by the Editorial Board.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1218219110/-/DCSupplemental.

Freely available online through the PNAS open access option.

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NF-κB inhibitor targets the endothelium
Bettina Sehnert, Harald Burkhardt, Johannes T. Wessels, Agnes Schröder, Michael J. May, Dietmar Vestweber, Jochen Zwerina, Klaus Warnatz, Falk Nimmerjahn, Georg Schett, Stefan Dübel, Reinhard Edmund Voll
Proceedings of the National Academy of Sciences Sep 2013, 201218219; DOI: 10.1073/pnas.1218219110

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NF-κB inhibitor targets the endothelium
Bettina Sehnert, Harald Burkhardt, Johannes T. Wessels, Agnes Schröder, Michael J. May, Dietmar Vestweber, Jochen Zwerina, Klaus Warnatz, Falk Nimmerjahn, Georg Schett, Stefan Dübel, Reinhard Edmund Voll
Proceedings of the National Academy of Sciences Sep 2013, 201218219; DOI: 10.1073/pnas.1218219110
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